Real-Life Advantages and Limits of Baricitinib for the Late Treatment of Adults Hospitalized with COVID-19

Round 1

Reviewer 1 Report (Previous Reviewer 1)

The authors have addressed most of the reviewers' concerns although the originality and overall merit of the research remains low.

Improved.

Author Response

Dear Reviewer,

Thank you for the comments and the time.

We have further improved the Manuscript by adding additional reviewers' suggestions that we have received after this last submission. On top of anything else, we improved the spelling and fluency of the English language by having the Manuscript double-checked by a fluent English speaker.

We are aware of the limits of our work. Nevertheless, it will add a little shred of evidence that could enlarge the current knowledge on using Baricitinib to treat COVID-19.

 

We hope it is suitable for publication in its current form.

 

Reviewer 2 Report (Previous Reviewer 2)

Novelty: 

Line [285 - 290] It appears that the author's results do not align with the conclusion drawn from other studies that combining Baricitinib and Remdesivir is more effective than using Baricitinib alone. However, since the author states that the data is limited, it is insufficient to disprove this conclusion and provide a contradictory one. Therefore, the author should be more specific on the goal and conclusion to explain the achivement of this study 

 

Data Limitation:

Two vaccines (and addition of 1-2 boosters) have been approved to be effective in preventing severe conditions from COVID-19. However, it is unclear why the author did not provide this information on whether patients had received the COVID vaccine and how many doses they had received. If this data cannot be obtained, it should be listed as a limitation. If the data is available, the author should control for this variable to rule out the effect of having received the vaccine, given that it is commonly acknowledged as the primary measure to avoid severe cases.

Moderate editing of English language

Author Response

Dear Reviewer,

Thank you for the observations.

• Novelty:

 

Our study aimed to highlight, using real-world data, all the limitations connected to using Baricitinib that Randomized Clinical Trials could not have shown due to their nature.

We have observed, in our cohort, a high prevalence of elderly subjects, in whom both age and the frequent presence of concomitant medical conditions contraindicated the use of Baricitinib.

Consequently, we have a treatment that, in theory, could be helpful and easy to use but, in practice, has limited applicability. 

A secondary aim of the study was to investigate whether the findings from RCTs regarding the efficacy of Baricitinib in improving the outcomes of patients hospitalized with COVID-19 and respiratory insufficiency could also be found in real-life. Concerning this point, our results confirmed what has already been highlighted by more extensive studies, even though, as underlined, our data were insufficient to prove the superiority of the association of Baricitinib + Remdesivir on the use of Baricitinib alone.

We have re-written the introduction and the conclusion section to address this concept better:

 

Introduction

“ (…) Aim of this study is to outline the applicability of immune-modulating treatment with Baricitinib in a real-life cohort of patients hospitalized with Sars-CoV2 pneumonia and oxygen requirement and highlight the possible limitations connected to its use that could not have adequately emerged from RCTs.

As a secondary aim, we will analyze the study population's clinical outcomes to understand the advantages of prescribing a specific medical treatment (Baricitinib, alone or in combination with Remdesivir), stated by the Guidelines, could also be obtained in real-life setting”.

 

Discussion

“All this considered, our study highlights how, despite the success of the vaccination campaign and the availability of early treatments, the risk of developing severe forms of COVID-19 requiring hospitalization is still high, at least for elderly and fragile subjects. In such cases, disposing of valid therapeutic alternatives capable of preventing disease progression is fundamental.

Our results strengthen the evidence that using Baricitinib helps improve the outcomes of patients with moderate/severe COVID-19.

However, our data show that old age, the presence of chronic kidney failure, and the short time of hospital admission from symptom onset often prevent in real life the prescription of Baricitinib in large part of patients with respiratory failure, who would, instead, benefit from the treatment. Paradoxically, it seems that just the current features of hospitalized patients with COVID-19 are the greater limit to the use of Baricitinib, which is prescribed on a case–by–case basis, according to the individual choice of the clinician.

Further studies with a prospective design, a more significant number of patients, and longer follow-ups are required to design new, different drugs capable of preventing the clinical progression of COVID-19 among fragile subjects who get infected and hospitalized, with the ultimate goal of improving their survival. "

 

• Data limitation:

 

Regarding vaccinal status, we have collected data on the proportion of vaccinated patients (intended as patients who had received at least two vaccine doses) and subjects who had received the booster dose. We already had this information reported in Table 1. However, we have also reported it in the Results section of the text, as reported below:

 

Results

“ (…) Out of 111 patients, 58 (52%) were vaccinate, 26 of whom (23%) had received vaccine booster dose. No significant difference was observed between treated and untreated patients with regard to the proportion of vaccinate individuals.”

 

We have also included vaccine status among the variables in the Cox regression analysis reported in Table 2. Notably, having received at least two vaccine doses was not a protective factor against poor outcomes, neither at univariate HR 2.15 (0.83-5.61, p=0.12) nor at multivariate analysis (HR1.13 95% C.I. (0.36-3.52, p=0.83). We included this information in the Results section for better clarity.

 

• Comments on the Quality of English Language:

 

We have had the Manuscript double-checked by a native English speaker to improve language fluency and consistency throughout the text.

 

Thank you for your comments and time.

 

 

 

Round 2

Reviewer 2 Report (Previous Reviewer 2)

the revision of the introduction and discussion parts from the authors addressed the questions in the first review. 

Minor editing of English language required

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

The manuscript by Poloseno al aims to evaluate the benefit of baricitinib in covid patients using a retrospective cohort. The following is a synopsis of concerns raised based on the data presented in the manuscript.

Major:

1) Page 3, lines 91-96. What does anti-viral mean? If anti-viral means remdesivir, why was remdesivir not given? Is baricitinib given to the patient within 7 days of symptom onset? Unclear what “not less than 7 days” mean.

2) Table 1, what’s the PaO2 of the patients when they enrolled?

3) Table 1, “dead” means death during hospitalization? Or within 21 or 28 days of admission? When the authors use “21 subjects (19%) died with a 165 rate of 29 x 100 patients-months follow-up.”

4) Figure 1 and Figure 2 have the same number of patients.

5) From Page 5 173 to page 6 189, which lines are figure legends?

6) Moderate language editing is required.

Author Response

Response to Reviewers

Reviewer 1:

The manuscript by Poliseno et al aims to evaluate the benefit of baricitinib in covid patients using a retrospective cohort. The following is a synopsis of concerns raised based on the data presented in the manuscript.

Major:

• Page 3, lines 91-96. What does anti-viral mean? If anti-viral means remdesivir, why was remdesivir not given? Is baricitinib given to the patient within 7 days of symptom onset? Unclear what “not less than 7 days” mean.

         Authors Response

         Dear Reviewer, thank you for your observation. “Antiviral” means Remdesivir. The drug          was not administered in the clinical context described in lines 91-96 (acute respiratory            failure who required HFNC or NIV at hospital admission) because International Guidelines          recommend the use of Remdesivir only in patients in low flow-oxygen (NIH COVID-19       Treatment Guidelines. Clinical spectrum of Sars-CoV-2 infection. (Last updated December               28, 2022)- Last accessed February 25, 2023). Baricitinib was only administered in patients          who reported symptoms of Sars-CoV2 infection from at least one week. Indeed, due to the immune-suppressive mechanism of action of the drug, its administration is not              recommended within the first seven days from symptoms onset, as it could significantly          reduce the host immune response and increase the viral replication. We have clarified the             concept in the Methods section.

         Methods:

         “(...) Baricitinib was prescribed at the dose of 4 mg QD or 2mg in case of impaired renal    function. Given the      immune-suppressive mechanism of action of the drug that could      significantly     reduce the host immune response and increase the viral replication if         administered close to symptoms onset, treatment was administered only in those subjects          reporting COVID-19 symptoms from at least 7 days.”

 

• Table 1, what’s the PaO2 of the patients when they enrolled?

         Authors Response

         Unfortunately, due to the retrospective nature of the study, we could not recall back          patients PaO2 at the moment of hospital admission. However, respiratory                insufficiency was intended as a ratio between PaO2 and FiO2 <150.

 

• Table 1, “dead” means death during hospitalization? Or within 21 or 28 days of admission? When the authors use “21 subjects (19%) died with a 165 rate of 29 x 100 patients-months follow-up.”

 

Authors Response

 

         Dear Reviewer,

         We reported deaths occurred during the course of hospitalization. rate of 29 x 100 patients    months follow up refers to the incidence of the          event death. We have re-written the              paragraph about the outcomes in the results section to better clarify these concepts

         Results

         “(…) After a median of 18 (12-23) days of hospital stay, 81 patients (73%) were discharged.      Over the course of hospitalization, 9 subjects (8%) were transferred in the Intensive Care           Unit (ICU) and 21 (19%) died (incidence rate of 29 x 100 patients-months Follow-Up).”

 

• Figure 1 and Figure 2 have the same number of patients.

 

Authors Response

 

Dear Reviewer,

Thank you for your point. The numbers of patients reported in the risktables under the Kaplan Maier curves in  Figure 1 and 2 are the same because they refers to the patients

at risk of developing the event of interest (which is admission in ICU, in Figure 1, or either ICU admission or death in Figure 2). At each landmark time (e.g. every 5 days) some patients will abandon the study (either due to discharge, transfer or death) and therefore they will be withdrawn from the group at risk. Those two Figures investigate the difference of survival probability between the same two groups  (treated and untreated patients), therefore the numbers of patients at risk follows the same trend in both figures.

 

 

• From Page 5 173 to page 6 189, which lines are figure legends?

         Authors Response

         Dear Reviewer,

         We are not sure we understand your request. However, from page 5 forward, the Figure              Legends are the following:

         Figure 1. Kaplan Meier estimates the 21-day probability of ICU admission in who received               standard care plus Baricitinib, alone or in combination with Remdesivir (Treated group).     Compared to the Untreated group, a lower risk (HR 0.10, 95% C.I. 0.01-0.86, Log-rank          p=0.03) of was reported among treated patients.

 

         Figure 2. Kaplan Meier estimates the 21-days probability of ICU admission/death in treated             patients Compared to the Untreated group, a lower risk (hazard ratio (HR) 0.39, 95% C.I.          0.15-1.01, p=0.04) of bad outcome was noticed among treated patients.

 

         Figure 3. Kaplan Meier estimates the 21-day probability of ICU admission/death in patients            treated with Baricitinib alone vs patients treated with Baricitinib and Remdesivir (RDV). No            significant difference (HR 0.74, 95% C.I. 0.14-4.05, p=0.73) was observed based on the type              of t treatment received.

 

• Moderate language editing is required.

 

Authors Response

 

Dear Reviewer, thank you for your advice.

We have double- checked the Manuscript to ensure consistency and fluidity throughout the text.

Reviewer 2 Report

The paper studied the data of patients hospitalized with moderate/severe COVID-19 between October 1st, 2021, and March 31st, 2022. Survival analyses were performed to estimate the 21-day probability of Intensive Care Unit (ICU) admission, death and the composite of the two with regard to the treatment received (Baricitinib, Baricitinib + RDV, None) and Cox regression analyses were performed to identify predictors of ICU admission/death among patients' features.

 

In general, the paper was clear in terms of the purpose of the study, the methodologies used in the study and the conclusions of the study.

 

Some minor issue:

• For the data input, were there pre-processing of the raw data to exclude some patients or 111 was the total number of subjects collected in the data?

 

• Line (112-114): The Chi-square test/Fisher exact test and non-parametric  ANOVA were used, as appropriate, to test the null hypothesis of no differences between groups. For each predictors in table 1, please clarify test that were used to determine the p-values.  The chi-squared test should be particularly avoided if there are few observations (e.g. less than 10) for individual cells.

 

• The survival analysis showed there is lower risk for people treated however no difference between people treated with different methods (Baricitinib vs.Baricitinib + RDV),  are there other existing literatures showing a similar or different results? What are their findings or explanations?

 

• The presence of Diabetes, CKD and chronic neurologic diseases were included in the cox models. Are there specific reason for the above conditions to be selected?

Author Response

Response to Reviewers

Reviewer 2:

The paper studied the data of patients hospitalized with moderate/severe COVID-19 between October 1st, 2021, and March 31st, 2022. Survival analyses were performed to estimate the 21-day probability of Intensive Care Unit (ICU) admission, death and the composite of the two with regard to the treatment received (Baricitinib, Baricitinib + RDV, None) and Cox regression analyses were performed to identify predictors of ICU admission/death among patients' features.

 

In general, the paper was clear in terms of the purpose of the study, the methodologies used in the study and the conclusions of the study.

 

Some minor issue:

 

• For the data input, were there pre-processing of the raw data to exclude some patients or 111 was the total number of subjects collected in the data?

 

Authors Response

 

Dear Reviewer, thank you for your observation.

111 was the total number of subjects collected in the dataset and it refers to all subjects consecutively admitted in the units of infectious and Respiratory Diseases during the study period.

 

 

• Line (112-114): The Chi-square test/Fisher exact test and non-parametric  ANOVA were used, as appropriate, to test the null hypothesis of no differences between groups.For each predictors in table 1, please clarify test that were used to determine the p-values.  

 

Authors Response

 

Dear Reviewer, your clarification was totally on point.

When the number of observations was <5, we used the Fisher Exact test, as specified in the Methods section. We have added the type of statistical test used for each variable among footnotes in Table 1, as requested.

 

• The survival analysis showed there is a lower risk for people treated however no difference between people treated with different methods (Baricitinib vs.Baricitinib + RDV), are there other existing literatures showing a similar or different results? What are their findings or explanations?

 

Authors Response

 

Dear Reviewer,

Thank you for your observation. Currently, both clinical trials and real-life studies show the superiority of the association of Baricitinib plus Remdesivir and possibly Dexamethasone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation (Kalil, A. C., Patterson, T. F., Mehta, A. K., Tomashek, K. M.,  and ACTT-2 Study Group Members (2021). Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19. The New England journal of medicine, 384(9), 795–807. https://doi.org/10.1056/NEJMoa2031994; Ngo, D. Q., Hamid, K., Rana, Het al. (2022). A Retrospective Study of Dexamethasone, Remdesivir, and Baricitinib in Severe COVID-19. The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale, 2022, 9209618. https://doi.org/10.1155/2022/9209618; Yasuda, Y., Hirayama, Y., Uemasu, K., Arasawa, S., Iwashima, D., & Takahashi, K. I. (2022). Efficacy of the combination of baricitinib, remdesivir, and dexamethasone in hypoxic adults with COVID-19: A retrospective study. Respiratory medicine and research, 81, 100903. https://doi.org/10.1016/j.resmer.2022.100903).

In light of these evidences, this treatment strategy is recommended by International Guidelines to be used in similar clinical context. Unfortunately, we were not able to demonstrate a better efficacy of the association of Baricitinib + Remdesivir vs Baricitinib alone, even though a slight lower hazard ratio  of ICU admission/ death was reported (HR 0.74, 95% C.I. 0.14-4.05, p=0.73). We do believe, given the wide Confidence Interval, that the small number of patients in the two groups (28 in the Baricitinib and 21 in the Baricitinib + Remdesivir group) could explain this statistic result.

 We have modified the Discussion section to include this clarification.

 

• The presence of Diabetes, CKDand chronic neurologic diseases were included in the cox models. Are there specific reason for the above conditions to be selected?

 

Authors Response

 

Dear Reviewer, thank you for your comment.

The variables that you mentioned were included in the multivariable Cox regression models as these comorbidities were the most frequently found among our study population and also because the frequent association of these factors with COVID-19 unfavorable outcome has often been observed in literature (Hu B, Guo H, Zhou P, Shi ZL. Characteristics of Sars-CoV-2 and COVID-19. Nat Rev Microbiol. 2021. 19(3):141-154. doi: 10.1038/s41579-020-00459-7 ; Wu, Z. & McGoogan, J. M. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in china: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020. 323, 1239–1242).

Reviewer 3 Report

 

1. The originality of the results is questionable. The efectivity of baricitinib in the treatment of COVID-19 has been assessed in clinical trials and other authors provided the data about real life effectiveness: 

Tziolos N, Karofylakis E, Grigoropoulos I, et al. Real-Life Effectiveness and Safety of Baricitinib as Adjunctive to Standard-of-Care Treatment in Hospitalized Patients With Severe Coronavirus Disease 2019. Open Forum Infect Dis. 2021;9(1):ofab588. Published 2021 Nov 22. doi:10.1093/ofid/ofab588

Lin Z, Niu J, Xu Y, Qin L, Ding J, Zhou L. Clinical efficacy and adverse events of baricitinib treatment for coronavirus disease-2019 (COVID-19): A systematic review and meta-analysis. J Med Virol. 2022;94(4):1523-1534. doi:10.1002/jmv.27482

It is not clear what the novel data the results provide. 

 

2. The results might be biased by the presence of comorbidities and age differences among treatment groups. The authors should perform multivariate analysis to counteract the effect of these cofounders. I don't understand why the Cox regression analysis contains other variables, not the baricitinib treatment. 

Round 2

Reviewer 1 Report

1. It is not clarified if baricitinib is discontinued after ICU admission and the medium dose/days patient received baricitinib

2. RDV is CIIa per NIH guideline for patients who are on HFNC or NIV. The practice of not administrating RDV to patients who are on HFNC/NIV is not consistent with practice guideline.

3. There is no guideline recommend withholding baricitinib in the first 7 days. The practice of not administrating RDV to patients who are on HFNC/NIV is not consistent with practice guideline.